Endogenous Cannabinoids in Inflammatory Airway Disease

炎症性气道疾病中的内源性大麻素

基本信息

批准号：
10532789
负责人：
Joshua M Levy
金额：
$ 7.83万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532789
关键词：
Adult Adverse reactions Affect Agonist Air Airway Disease American Anaphylaxis Aspirin Asthma Award Biochemical Biological Assay Biological Markers Biometry CNR2 gene Caring Chronic Clinical Clinical Research Data Development Diagnosis Diagnostic Disease Doctor of Philosophy Dose Drug Screening Drug Targeting Electrical Resistance Endocannabinoids Enzyme Inhibitor Drugs Epithelial Cells Epithelium Face Funding Future Genetic Transcription Health Health Expenditures Human Inflammation Inflammatory Ingestion Institution Intervention Investigation Laboratories Leadership Leukocytes Leukotrienes Life Liquid substance Logistic Regressions Lung diseases Mediator Mentorship Modeling Nasal Epithelium Nasal Polyps Non-Steroidal Anti-Inflammatory Agents Observational Study Operative Surgical Procedures Patient Care Patients Pharmaceutical Preparations Physicians Population Positioning Attribute Procedures Prostaglandin-Endoperoxide Synthase Provider Reaction Reporting Research Design Resources Role Sampling Scientist Screening procedure Secure Series Sinus Site Symptoms Syndrome Testing Therapeutic Time Tissues United States United States National Institutes of Health Validation Work Writing accurate diagnosis airway inflammation airway remodeling allergic airway disease aspirin-exacerbated respiratory disease asthmatic base biobank biomarker identification biomarker panel cannabinoid receptor career clinical diagnostics clinical practice cofactor comorbidity cost cyclooxygenase 2 cytokine design diagnostic biomarker diagnostic criteria diagnostic strategy disease diagnosis drug discovery emerging adult experience high risk human model improved in vitro Model innovation insight migration new therapeutic target novel novel diagnostics novel marker participant enrollment pre-clinical response screening panel skills small molecule translational scientist translational study treatment strategy

项目摘要

Abstract This proposal details a two-year plan to prepare the candidate, Joshua M Levy, MD, MPH, for a career as an independent translational investigator positioned to advance our understanding of asthma and allergic airway disease. The proposed investigations focus on the role of endogenous cannabinoids as mediators of upper and lower airway inflammation in Aspirin-exacerbated respiratory disease (AERD). AERD is clinically characterized by moderate to severe asthma, nasal polyps and anaphylactoid reactions to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin challenge represents the gold-standard to diagnose AERD, but is poorly utilized due to limited availability of specialized providers and concerns of adverse reactions to the procedure. Therefore, up to 42% of patients with asthma and nasal polyps fail to receive an accurate diagnosis of AERD, resulting in inadequate treatment marked by multiple sinus surgeries, irreversible airway remodeling and an annual U.S. healthcare expenditure of >$4.5 billion. The candidate has identified increased expression of the endogenous type-2 cannabinoid receptor in AERD nasal polyp epithelium, a novel finding that is independent of tissue inflammation and holds potential to advance patient care via the development of innovative diagnostic and treatment strategies. Employing an observational study design with cellular and biochemical approaches, the candidate will test the hypotheses that endogenous cannabinoid (endocannabinoid) dysregulation is associated with airway inflammation in AERD and represents a novel target for diagnosis and drug discovery. These studies will advance our understanding of AERD while developing both a biomarker screening panel and preclinical evidence lending support for the trial of endocannabinoid-directed therapeutics in this disease. During the period of support the candidate will leverage his clinical experience in the diagnosis and treatment of AERD, the regional referral patient base at his institution's AERD Center, and his laboratory skills while further developing skills in clinical study design, advanced biostatistics, team leadership, and scientific writing. These skills will enable his transition to independence with the submission of R01 proposals during the second year of this award. Dr. Levy will work collaborator Andrew A. White at Scripps Health, a national leader in the clinical study of AERD to further support the feasibility of rapid study completion. Additional support in the form of continued mentorship will be provided by David M. Guidot, MD, an expert in the translational study of lower airway disease in chronic inflammatory states. Additionally, Dr. Levy has assembled a team of extraordinary PhD and physician collaborators, including Drs. Michael H. Koval and Reneé H. Moore, who have committed their time and resources to facilitate the successful completion of this study. Completion of this translational study will position the candidate to secure independent NIH funding and establish himself as a physician-scientist with a focus on clinical and translational studies of endogenous cannabinoids in AERD and other forms of asthma.

抽象的该建议详细介绍了一项为期两年的计划，以准备候选人Joshua M Levy，MD，MPH 独立翻译调查员的阳性者的位置，以提高我们对哮喘和过敏性气道的理解疾病。阿司匹林呼吸道疾病（AERD）中的气道炎症以中度至重度哮喘为特征，鼻息音对阿司匹林和其他非甾体类抗炎药（NSAIDS）。 AERD，但由于专业提供者的可用性有限和不利的担忧，最近使用的情况很差因此，对该程序的反应。精确诊断AERD，导致多次鼻窦手术的治疗不足，不可逆气道改建和年度医疗保健支出> 45亿美元。在Aerd鼻息息质中，内源性2型大麻素受体的表达增加，这是一种新型发现与组织炎症无关，并具有通过开发创新的诊断和信任策略。细胞和生化方法，候选人将测试内源性大麻素的假设（内源性大麻素）失调与气道炎症有关，代表一个新颖的诊断和药物发现的目标。开发生物标志物筛选面板和临床前证据贷款支持内源性大麻素指导的治疗疗法。他在AERD诊断和信任方面的临床经验，AERD是他的区域转诊患者基础机构的AIRD中心及其实验室技能，同时进一步发展临床研究设计的技能，高级生物统计学，团队领导和科学写作将使他的过渡到在此期间的第二年，独立于R01提案。 Scripps Health的合作者Andrew A. White 支持快速研究完成的可行性。由医学博士David M. Guidot提出，这是慢性气道疾病转化研究的经验炎症状态。合作者，包括Drs。促进成功压缩的资源。候选人获得独立的NIH资金并确立自己为医师科学家的候选人，重点是 AERD和其他形式的哮喘中内源性大麻素的临床和翻译研究。